21:T459,PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T_ex) or nonexhaustion signatures (T_non-ex). Among skewed clonotypes, those in the T_ex, but not those in the T_non-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T_ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T_ex clonotypes, mainly from TDLNs.22:T4e1,Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8⁺ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8⁺ T cells, induces CD4⁺ follicular helper T (T_FH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the T_FH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. T_FH-like cytotoxic CD4⁺ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic T_FH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8⁺ T cells, respectively. Our findings provide deep insights into T_FH-like CD4⁺ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8⁺ T cells.23:T5c3,

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